Vaccine: adverse events linked to 'nocebo' effect, the negative expectancy reaction after administration, investigated

The ‘nocebo’ effect: reaction triggered by negative expectation after drug or placebo administration

“The research group coordinated by Professor Martina Amanzio of the Department of Psychology of the University of Turin, in collaboration with prestigious national (Department of Neuroscience, NEUROFARBA – Section of Psychology, University of Florence) and international research centres, located in the United States (Department of Psychiatry and Human Behavior, Brown University) and in Greece (Department of Neurology, Aeginition Hospital, National and Kapodistrian University of Athens), published a scientific study in the authoritative journal The Lancet Regional Health – Europe, which reveals, in accordance with the cognitive theory of expectation, how the adverse events detected in clinical trials of Covid-19 vaccines are associated with a nocebo effect.

What is a nocebo effect?

The term refers to a negative reaction – less described than its opposite, the placebo response – characterised by the expression of side effects largely prompted by the expectation of the occurrence of adverse events following the administration of a drug or placebo,” reads the note issued by the University of Turin (UK).

“The Amanzio-led research group is the first to investigate adverse events associated with clinical trials of SARS-CoV-2 vaccines.

It identified three vaccine trials approved by regulatory bodies in the EU (EMA) and the US (FDA): two mRNA-based (38,403 participants) and one adenovirus-based (6,736 participants).

In particular, safety data (phase III) were analysed with respect to side effects elicited in the placebo, saline-treated, and active drug groups, taking into account two mRNA vaccines (BNT162b2 and mRNA-1273 from Pfizer and Moderna, respectively) and one adenovirus vaccine (Ad26.COV2.S from Janssen / Johnson & Johnson).

The results of the study showed a commonly occurring incidence of adverse events in all trials, in the placebo and active drug groups.”

Adverse events (AEs) of drugs are a central feature of safety assessment information,” the United Kingdom points out.

It is well known that randomised clinical trials (RCTs) provide a perspective for understanding the role of negative expectations on subjects who know they may receive a drug that will promote the occurrence of AEs.

In RCTs it is known that drugs that produce more AEs also cause more side effects in placebo groups and consequently higher drop-out rates.

The AEs studied in placebo groups by administration of saline are described in terms of a nocebo response, which is common in clinical practice.

Why these AEs occur is unclear and understanding the underlying mechanisms is an ongoing challenge.

Symptoms found in placebo groups may be due to negative expectations and cause physical and mental health risks associated with the nocebo effect, as highlighted by a recent neuroscientific study by Professors Fabrizio Benedetti and Martina Amanzio’.

What contributes to the nocebo effect?

However, no study has so far investigated the nature of AEs in relation to SARS-CoV-2 vaccines,” adds Unito, “and the extent to which they are attributable to the nocebo effect.

With this in mind, Prof. Amanzio and other researchers analysed ‘prompted’ adverse reactions, referring to a list of symptoms that participants reported using electronic diaries – within seven days of placebo or vaccine inoculation.

In addition, ‘unsolicited’ AEs (spontaneously reported within 28 days after injection) were assessed in terms of Serious Adverse Events (SAEs) in all groups of the three selected studies.

The results showed a profile of solicited AEs in the placebo arms comparable to that of the vaccine, although the percentage was higher in the active groups.

The most frequently reported stressed AEs were fatigue, headache, local pain as a reaction to the injection site, and myalgia/muscle pain.

Specifically, compared to the first doses, fatigue was reported by 21-29% in the placebo groups and 37-42% in the active drug groups; headache by 24-27% and 33-39% in the placebo and active drug groups respectively; and muscle pain by 10-14% in the placebo groups and 18-33% in the active drug groups.

Injection site reactions were also common: 12-17% in the placebo and 48-84% after active drug.

AEs of fatigue, headache and pain were more common in the younger population and for the first doses of the mRNA vaccines (both in the placebo and active drug groups).

Other adverse events, present in both groups (placebo and active), were reported less frequently.

In general, younger subjects were more likely to report adverse events.

SAEs were defined as in line with the expected rate of occurrence in the general population and not related to vaccination.

“Although there is a higher incidence of AEs in the vaccine groups,” explains the Athenaeum, “compared to the placebo groups, it is clear that most of these side effects are not due to the vaccine per se but can be attributed to the effect of the nocebo”.

“The results suggest that a substantial proportion of solicited AEs are not a result of the vaccine per se, but are due to the effect of the nocebo”

“In studies of new vaccines, increased awareness of the nocebo response, in placebo groups, may lead to greater participation in immunisation and greater protection from SARS-CoV-2 infection, limiting fear and anxiety about the safety of these new drugs.

The publication is accompanied by a prestigious ‘Commentary’ by Prof. Peter Sever of the National Heart and Lung Institute – of Imperial College London.”

“Highlighting the importance of the nocebo response associated with the current SARS-CoV-2 vaccination at an early stage is very important.

In many countries where the vaccine has been made available there is a significant minority who refuse to be immunised.

Most of these individuals are poorly informed about the safety of the vaccine, its ability to protect against severe SARS-CoV-2 infection, and the importance of achieving group immunity.

Our publication adds an important piece of information about adverse reactions to the vaccine.

It would be desirable for physicians to use this knowledge to make their patients aware of the need to adhere to Covid-19 vaccination,” concludes Professor Martina Amanzio.

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